An important clinical trial candidate, (6R, 7S) 7-(R)-phenylglycylinamido-3-chloro-1-azabicyclo[4.2.0]-oct-2-en-8-on-2-car boxylic acid (loracarbef) may be synthesized by various routes. One of the more noteworthy total syntheses of loracarbef is that made possible by Evans and Sjogren, U.S. Pat. No. 4,665,171. The Evans and Sjogren methodology provides a chiral 2+2 (ketene plus imine) cycloaddition, and accordingly, entry to a wide variety of chiral cis .beta.-lactams. However, the Evans and Sjogren methodology provides for the utilization of a chiral auxiliary of the formula ##STR1## in the 2+2 cycloaddition with a Schiff's base, wherein X' is chloro, bromo, trifluoroacetoxy, or -OP(=)X.sub.2, wherein X is halogen. The above chiral auxiliary is synthesized in seven steps from L-phenylglycine. The resulting cycloaddition provides compounds of the formula ##STR2## wherein Ar is phenyl, C.sub.1 -C.sub.4 alkylphenyl, halophenyl, C.sub.1 -C.sub.4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl, or benzofuryl; R is phenyl, C.sub.1 -C.sub.4 alkylphenyl, C.sub.1 -C.sub.4 alkoxyphenyl, or halophenyl; Y is --CH.dbd.CH--, or --CH.sub.2 --CH.sub.2 --; and R' is phenyl, C.sub.1 -C.sub.4 alkylphenyl, C.sub.1 -C.sub.4 alkoxyphenyl, halophenyl, furyl or naphthyl.
The obvious shortcomings of the Evans and Sjogren route are that a very expensive starting material, L-phenylglycine, is used, the chiral auxiliary is synthesized in several steps in linear fashion; and further, the chiral auxiliary is removed and discarded using Li/NH.sub.3 /t-C.sub.4 H.sub.9 OH to provide a free 3-aminoazetidinone.
As an achiral alternative, Hatanaka et al., Tetrahedron Letters Vol. 24, No. 49, pp 4837-4838 (1983), provides a method of preparing a 3-hydroxy(.+-.)-1-carbacephalosporin via a 2+2 cycloaddition much in the same fashion as that of Evans and Sjogren, but without the use of a chiral auxiliary as the ketene source. The Hatanaka methodology provides many of the same intermediates as does the Evans and Sjogren synthesis, albeit in achiral form. The advantage of the achiral synthesis is economy of steps and starting material.
The present invention affords a useful alternative to the challenge of synthesizing 1-carba(1-dethia)cephalosporins by providing a method for resolution of a key achiral cis-azetidinone intermediate provided by achiral cis-2+2 cycloaddition. In particular, the present invention provides a method for resolution of a crucial achiral intermediate in the total synthesis of 1-carba(1-dethia)cephalsoporins using L-malic acid.